Autoimmunity and emphysema and risk of osteoporosis in smokers

吸烟者的自身免疫和肺气肿以及骨质疏松症的风险

• 批准号: 9916794
• 负责人: JESSICA BON
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916794
• 关键词: Age; Alveolar Macrophages; Antibodies; Autoantibodies; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Binding Proteins; Biological Assay; Biological Markers; Bone Density; Cachexia; Cause of Death; Cells; Chronic Obstructive Airway Disease; Data; Dentin; Diagnostic radiologic examination; Disease; Disease Progression; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Female; Foundations; Fracture; Future; Goals; Heat shock proteins; High Prevalence; Human; Immune Targeting; Immune response; Immunoglobulin G; Immunohistochemistry; Immunologic Markers; Immunologics; Immunomodulators; In Vitro; Incidence; Inflammation Mediators; Inflammatory; Investigational Therapies; Link; Literature; Longitudinal cohort; Lung diseases; Measurement; Measures; Mediating; Molecular; Molecular Chaperones; Morbidity - disease rate; NF-kappa B; Natural History; Osteoclasts; Osteoporosis; Osteoporosis prevention; Participant; Pathogenesis; Pathogenicity; Pathologic; Patient Selection; Patients; Physical activity; Physiological; Population; Prevalence; Prevention strategy; Process; Production; Proteins; Pulmonary Emphysema; Reaction Time; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Risk stratification; Roentgen Rays; Role; Scanning; Series; Smoker; Smoking Status; Stains; Steroids; Testing; United States; Variant; Woman; X-Ray Computed Tomography; airway obstruction; biological adaptation to stress; bone; bone resorbing activity; bone turnover; clinically significant; cohort; cytokine; endoplasmic reticulum stress; falls; follow-up; glucose-regulated proteins; improved; insight; male; men; mortality; novel; nuclear factors of activated T-cells; osteoporosis with pathological fracture; patient population; physical inactivity; precursor cell; public health relevance; pulmonary function; response; screening guidelines; smoking-related lung disease; targeted agent; tartrate-resistant acid phosphatase; time interval; tool; treatment strategy

 DESCRIPTION (provided by applicant): Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.

 描述(由申请人提供)：低骨密度(BMD)与慢性阻塞性肺疾病(COPD)有关，与传统的骨质疏松症风险因素无关，包括类固醇使用、恶病质和体力活动减少。尽管骨质疏松症患病率的增加增加了COPD患者的发病率和死亡率，但对这一易感人群中骨密度评估的适应症或骨质疏松机制知之甚少。骨密度损失率是骨折的独立危险因素。然而，双X射线骨密度仪(DXA)对骨密度的横断面评估没有提供关于骨密度下降率的信息。免疫改变在COPD和骨质疏松症的发病机制中均有作用，但自身免疫在COPD相关性骨质疏松症中的作用尚未被研究。文献支持肺气肿与低骨密度之间的独立关联，但这种关联的机制也不清楚。该项目的总体目标是研究特定的自身免疫过程如何与合并肺气肿进展和患有肺部疾病的男性和女性吸烟者的骨密度加速下降有关。这一目标将通过将已经建立的纵向队列延长到六年来实现，该队列具有预先存在的基准和对骨密度、放射学肺气肿、肺功能和自身免疫生物标记物水平的两年评估。一种自身免疫生物标记物--抗糖调节蛋白78(GRP78)免疫球蛋白(GRP78)与肺气肿进展(通过定量CT扫描测量)和骨密度丢失(通过系列DXA测量)在六年时间间隔内的相关性将在患有肺气肿或气流阻塞的吸烟者中进行研究。将进行一系列体外破骨细胞研究，以评估GRP78自身抗体对破骨细胞形成、增殖和活性的影响。GRP78是一种与内质网(ER)应激反应密切相关的内质网伴侣蛋白。这个项目的发现将 为有加速骨密度丢失风险的吸烟者确定标准，早期和连续测量骨密度，为肺气肿和骨质疏松症的发病机制提供洞察，并为COPD患者的骨质疏松症预防和治疗策略提供新的靶点。